Regulation of the stability and transcriptional activity of NFATc4 by ubiquitination
Regulation of the stability and transcriptional activity of NFATc4 by ubiquitination
复制标题
DOI：
10.1016/j.febslet.2008.11.009
复制
发表时间：
2008-12-10
期刊：
影响因子：
3.5
通讯作者：
Li, Huihua
中科院分区：
文献类型：
--
作者：
Fan, Yongna;Xie, Ping;Li, Huihua
活化T细胞核因子（NFATc 4）是心脏发育和肥大的关键调节因子。然而，调节NFATc 4稳定性和反式激活的机制仍不清楚。我们发现NFATc 4蛋白主要通过形成赖氨酸48连接的多聚泛素链而被泛素化，并且这种修饰降低了NFATc 4蛋白水平及其转录活性。此外，激活GSK 3 β显著增强NFATc 4泛素化并降低其反式激活，而抑制GSK 3 β则具有相反的效果。重要的是，由GSK 3 β诱导的泛素化和磷酸化抑制NFATc 4依赖性心脏特异性基因表达。这些结果表明，泛素-蛋白酶体系统在调节NFATc 4的稳定性和反式激活中起着重要作用。
Nuclear factor of activated T cells (NFATc4) has been implicated as a critical regulator of the cardiac development and hypertrophy. However, the mechanisms for regulating NFATc4 stability and transactivation remain unclear. We showed that NFATc4 protein was predominantly ubiquitinated through the formation of Lysine 48-linked polyubiquitin chains, and this modification decreased NFATc4 protein levels and its transcriptional activity. Furthermore, activation of GSK3 beta markedly enhanced NFATc4 ubiquitination and decreased its transactivation, whereas inhibition of GSK3 beta had opposite effects. Importantly, ubiquitination and phosphorylation induced by GSK3 beta repressed NFATc4-dependent cardiac-specific gene expression. These results demonstrate that the ubiquitin-proteasome system plays an important role in regulating NFATc4 stability and transactivation.